Rhabdomyosarcoma is a muscle cancer that occurs in children. Previous research has shown that activation of a protein called YAP is a key cause of rhabdomyosarcoma, however how activation occurs is still unknown. This project is investigating how activation of YAP happens, and also if the protein has the potential to be used as a drug target. If we can understand how YAP turns on, we can work out how to turn it off.
Causes and therapeutic implications of YAP activity in embryonal rhabdomyosarcoma
Rhabdomyosarcoma is a devastating muscle cancer that occurs in infants and children. In our previous work that was part funded by Sarcoma UK we have shown that a protein termed YAP is present and active in this type of cancer. When we artificially activate YAP in mouse muscle stem cells, all mice developed rhabdomyosarcoma. Additionally, when we reduced YAP levels in human rhabdomyosarcoma cells then they switched from cancer cells into cells that resemble normal muscle. Whilst this research has identified YAP as a key cause of rhabdomyosarcoma we were unable to identify the mechanism that causes YAP activation.
The aim of the proposed study is therefore to investigate the activation of YAP in rhabdomyosarcoma and additionally its usefulness as a drug target. First we wish to study whether common changes in the DNA sequence of rhabdomyosarcoma cells can activate YAP.
Second we plan to study whether YAP is necessary for the cancer-related functions of common DNA variations in rhabdomyosarcoma. Third we plan to test whether we can use YAP-inhibiting drugs to achieve similar anti-cancer effects that we previously observed when we reduced YAPn. Finally, we wish to breed and investigate transgenic zebrafish that form rhabdomyosarcomas. These rhabdomyosarcomas become fluorescent when YAP is active which for example allow us to study drugs that inhibit YAP in rhabdomyosarcoma.
- Matallanas, D. et al. (2017) Common and Distinctive Functions of the Hippo Effectos Taz and Yap in Skeletal Muscle Stem Cell Function. Stem Cells 35(8). Read more: http://aura.abdn.ac.uk/bitstream/handle/2164/9092/Sun_et_al_2017_STEM_CE...
- Mohamed, A. D. et al. (2018) Analysis of the relationship between the KRAS G12V oncogene and the Hippo effector YAP1 in embryonal rhabdomyosarcoma. Scientific Reports. Read more: https://www.nature.com/articles/s41598-018-33852-7
- The Hippo effector TAZ (WWTR1) transforms myoblasts and its abundance is associated with reduced survival in embryonal rhabdomyosarcoma. Poster presented at the Goodbye Flat Biology: Models, Mechanisms and Microenvironment Conference. October, 2016. Berlin, Germany.
- The Hippo effector TAZ (WWTR1) transforms myoblasts and its abundance is associated with reduced survival in embryonal rhabdomyosarcoma. Poster presented at the Sarcoma Research Symposium (Basic Science). September, 2016. London, UK.
Presentations & Workshops
- Zebrafish training workshop ran at Karlsruhe Institute of Technology. March, 2016. Karlsruhe, Germany.
- Live cell imaging workshop ran at The University of East Anglia. June, 2016. Norwich, UK.
- Causes and therapeutic implications of YAP in embryonal rhabdomyosarcoma. Presentation given at the Oxford Hippo Symposium, University of Oxford. December, 2016. Oxford, UK.
- The Hippo pathway in muscle related diseases. Presentation given at the Hippo Symposium, Munich. November, 2016. Munich, Germany.
- The Hippo pathway in childhood cancer. Presentation given at the Helmholtz Centre. 2017. Munich, Germany.